Genetic analysis of the Dutch Hunger Winter Families Study to Boost Rigor and Robustness for Testing In-Utero Famine Effects on Aging-Related Health Conditions and Biological Aging

荷兰饥饿冬季家庭研究的遗传分析，以提高测试宫内饥荒对衰老相关健康状况和生物衰老影响的严谨性和稳健性

• 批准号: 10410379
• 负责人: Daniel Walker Belsky
• 金额: $ 51.21万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410379
• 关键词: Accounting; Address; Adult; Affect; Age; Aging; Animal Experiments; Biological; Biological Aging; Biological Assay; Birth; Birth Rate; Blood; Blood specimen; Cardiometabolic Disease; Characteristics; Child; Chronic Disease; Clinical; Cognitive; Conceptions; DNA Methylation; DNA Sequence; Data; Databases; Development; Disease; Elderly; Epigenetic Process; Event; Exposure to; Family Study; Famines; Fertility; Fetal Growth Retardation; Fetal Mortality Statistics; Future; Genetic; Genetic Variation; Genomics; Genotype; Goals; Health; Human; Hunger; Individual; Infant; Intervention; Knowledge; Life; Life Cycle Stages; Link; Long-Term Effects; Longevity; Measures; Mediator of activation protein; Methylation; Modeling; Natural experiment; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Observational Study; Onset of illness; Outcome; Participant; Pathology; Pathway interactions; Perinatal; Plant Roots; Population; Prevention strategy; Process; Publishing; Quantitative Trait Loci; Research; Resources; Risk; Sampling Studies; Selection Bias; Siblings; Survivors; Testing; Time; War; Work; age related; base; cardiometabolism; cognitive reserve; cognitive testing; cohort; evidence base; fetal; follow-up; genetic analysis; genetic approach; genetic information; genetic selection; genetic testing; genetic variant; genome wide association study; genome-wide; healthspan; improved; in utero; knowledge base; member; multiple omics; novel strategies; perinatal period; polygenic risk score; prenatal; prevent; randomized trial; study population; treatment strategy; unethical; whole genome

SUMMARY The graying global population makes interventions to extend healthy lifespan a public heath priority. Health insults during the perinatal period are linked with risk for aging-related health conditions, including obesity, type 2 diabetes, and cardio-metabolic disease. If these associations are causal, interventions to prevent perinatal insults and to reverse their biological damage could delay disease onset and prolong healthspan. However, establishing causal long-term health effects of perinatal insults in humans is challenging. Randomized trials would be unethical. Observational studies can be biased by confounding factors that erroneously suggest a link between insults in the perinatal period and later health. In contrast, natural experiments can isolate the impact of perinatal insults on adult disease and healthspan. The Dutch Hunger Winter Families Study (DHWFS) uses a sudden, war-induced famine as a natural experiment. The famine was caused by a Nazi blockade during WWII in 1944-45. Because the impact of famine was immediate, transient, and population- wide, DHWFS comparison of infants born during the famine with those born before or after the famine will identify potential long-term effects of perinatal-insults. However, famine natural-experiment studies, including DHWFS, may be vulnerable to selection bias. Birth rates decline significantly during famine; famine’s impact on fertility and fetal/infant survival might bias famine studies of perinatal insult’s long-term effects in unknown ways. To fill this gap in knowledge, we will genotype stored DHWFS biospecimens from of N=956 individuals, 37% of whom were exposed to famine in-utero and the remainder of whom are siblings of the famine-exposed individuals and “time controls” born immediately before or after the famine. We will link new genetic data with participants’ existing clinical and cognitive tests and blood DNA methylation data. We will examine in this integrative multi-omics database the potential impact of selective fertility and fetal/infant survival during the famine on (i) genome wide genetic characteristics; (ii) differences in polygenic risk scores for specific aging- related health conditions; and (iii) differences in methylation quantitative trait loci (mQTL) genotypes. We will then conduct genetics-informed analysis of famine effects on obesity, type-2 diabetes, cognitive reserve, and epigenetic aging. Using these new resources, we will prepare an integrated multi-omics database of the DHWFS population for use by outside research teams and generate a one of a kind resource for famine and perinatal insult research. The proposed project will generate a new knowledge base to further examine biological pathways that are likely to connect perinatal events to adult health and aging through genetic and epigenetic mechanisms.

概括 全球人口老龄化使得延长健康寿命的干预措施成为公共卫生优先事项。 围产期的侮辱与衰老相关健康状况的风险有关，包括肥胖、类型 2 糖尿病和心脏代谢疾病 如果这些关联是因果关系，则需要采取干预措施来预防围产期。 侮辱并扭转其生物损伤可以延缓疾病的发作并延长健康寿命。 确定围产期侮辱对人类健康的长期因果影响具有挑战性。 观察性研究可能会因混杂因素而产生偏差，从而错误地得出结论。 相比之下，自然实验可以分离出围产期的侮辱与以后的健康之间的联系。 围产期侮辱对成人疾病和健康寿命的影响荷兰饥饿冬季家庭研究。 （DHWFS）使用一场突然的、战争引起的饥荒作为自然实验。饥荒是由纳粹造成的。 1944-45 年第二次世界大战期间的封锁，因为饥荒的影响是直接的、短暂的和人口减少的。 DHWFS 对饥荒期间出生的婴儿与饥荒之前或之后出生的婴儿进行广泛比较 然而，饥荒自然实验研究，包括确定围产期侮辱的潜在长期影响。 DHWFS，可能容易受到饥荒影响期间出生率显着下降的影响。 生育力和胎儿/婴儿存活率可能会使围产期侮辱对未知情况的长期影响的饥荒研究产生偏差 为了填补这一知识空白，我们将对 N=956 个人中存储的 DHWFS 生物样本进行基因分型， 其中 37% 在子宫内经历过饥荒，其余的人是遭受饥荒的兄弟姐妹 我们将把新的基因数据与饥荒之前或之后出生的个人和“时间控制”联系起来。 我们将在此检查参与者现有的临床和认知测试以及血液 DNA 甲基化数据。 综合多组学数据库选择性生育和胎儿/婴儿存活率的潜在影响 饥荒对（i）全基因组遗传特征；（ii）特定衰老的多基因风险评分的差异 相关的健康状况；以及 (iii) 甲基化数量性状基因座 (mQTL) 基因型的差异。 然后对饥荒对肥胖、2 型糖尿病、认知储备和认知储备的影响进行遗传学分析 利用这些新资源，我们将准备一个综合的多组学数据库。 DHWFS 人口供外部研究团队使用，并为饥荒和饥饿问题生成一种独一无二的资源 拟议的项目将产生一个新的知识库来进一步检查。 可能通过遗传和衰老将围产期事件与成人健康和衰老联系起来的生物途径 表观遗传机制。